Lifestyle, Inflammation, and Vascular Calcification in Kidney Transplant Recipients
Sotomayor, Camilo G.
DOI:
10.33612/diss.135859726
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Publication date: 2020
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Sotomayor, C. G. (2020). Lifestyle, Inflammation, and Vascular Calcification in Kidney Transplant Recipients: Perspectives on Long-Term Outcomes. University of Groningen.
https://doi.org/10.33612/diss.135859726
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Chapter 9
Lifestyle, Infl ammation, and Vascular Calcifi cation
in Kidney Transplant Recipients:
LIFESTYLE, INFLAMMATION AND VASCULAR
CALCIFICA-TION IN KIDNEY TRANSPLANT RECIPIENTS: PERSPECTIVES
ON LONG-TERM OUTCOMES
T
he role of lifestyle-related factors including diet and exposure to toxic contaminants is an underexplored area of investigation in the kidney transplantation fi eld.1–6 Beyond hazards of immunological nature, a systematic assessment of potentially modifi able —yet rather overlooked— risk factors for the long-standing high risk of graft failure beyond the fi rst-year post-transplant and on the excess cardiovascular risk of kidney post-transplant recipients (KTR), may reveal novel targets for clinical intervention to optimize long-term health and downturn current rates of premature death. It should also be taken into account that while kidney transplantation aims to restores kidney function, it incompletely mitigates mechanisms of disease such as chronic low-grade infl ammation with persistent redox imbalance, and deregulated mineral and bone metabolism.7–26 In addition to pro-infl ammatory eff ects of various degrees of uraemia, a chronic low-grade immunologic response to the kidney allograft, and the unavoidable long-term toxicity of maintenance immunosuppressive therapy further feed and perpetuate these mechanisms of disease.12,13,27–43 Remarkably, while the vicious circle between infl ammation and oxidative stress as common fi nal pathway of a multitude of insults plays an established pathological role in native chronic kidney disease (CKD), its characterization post-kidney transplant has been less than satisfactory. Next to a chronic infl ammatory status, markedly accelerated vascular calcifi cation persists after kidney transplantation, and is likewise suggested a major independent mechanism of which its mitigation may counterbalance the excess risk of cardiovascular disease post-kidney transplant.17,23,44The aim of this thesis was two-fold. First, we aimed to assess whether modifi able dietary elements and toxic environmental contaminants may explain increased risk of cardiovascular mortality and late graft failure in KTR. Next, we aimed to investigate specifi c laboratory and clinical readouts with a proposed role within persisting mechanisms of disease post-kidney transplantation (i.e., infl ammation and redox imbalance, and vascular calcifi cation), as potential non-traditional risk factors for adverse long-term outcomes in KTR.
9
SUMMARY
Part I — Lifestyle; Healthy Diet & Toxic Contaminants
In chapter 2 we analyzed the association and interaction of fruits and
vegetables consumption with estimated glomerular fi ltration rate (eGFR) and proteinuria on risk of cardiovascular and overall mortality in a population of kidney transplant recipients (KTR) with a functioning graft ≥1 year. In this study, we found that relatively higher vegetable consumption (e.g. a relative increase of 1 tablespoon of vegetables per day) is strongly associated with lower risk of cardiovascular and overall mortality in KTR (~50% and ~25% decreased risk, respectively). Noteworthy, this association was independent of socioeconomic status, physical activity, traditional cardiovascular risk factors, eGFR and proteinuria. Vegetables contain fi ber, vitamin A, vitamin C, vitamin K, and phytochemicals such as carotenoids and the broad group of polyphenols including phenolic acids and fl avonoids.45 Indeed, the inverse association between vegetable consumption and cardiovascular risk has largely and consistently been reported in epidemiological studies over general population.46–63
In the clinical setting of pre-transplant end-stage renal disease (ESRD), patients have long been advised to avoid fruit and vegetables consumption to limit potassium intake, and there is no clear clinical incentive — likely due to lack of evidence — to prescribe liberation of fruits and vegetables consumption post-kidney transplant.64 Indeed, underscoring the claim that systematic assessment is needed to accurately translate a priori benefi ts of a diet higher in fruits and vegetables to CKD patients, we found an independent inverse association of fruit consumption on risk of cardiovascular mortality, although particularly within KTR with eGFR >45 mL/min/1.73 m2 or absence of proteinuria.
It should be noted, nevertheless, that within the subgroup of KTR with lower eGFR or with proteinuria, a higher fruit consumption did not associate with increased mortality risk. This is a fi nding of paramount relevance. KTR are patients that have been largely advised and trained to avoid fruits and vegetables because these food items tend to have the highest concentration of potassium, which may lead to an increased risk of hyperkalaemia as eGFR declines, which is, in turn, a potentially life-threatening condition because of the associated risk of ventricular arrhythmia and cardiac arrest.65–67 However,
it has been observed that rich-potassium plant-based diets have not shown to induce hyperkalemia in CKD patients, likely due to a concomitant high-fi ber content that facilitates gastrointestinal transition, allowing less potassium to be absorbed.64,68–73 Moreover, the health benefi ts of fruits and vegetables rich in potassium may be related to their alkalinizing eff ects, as supported by previously observed reductions in metabolic acidosis, even in nondiabetic CKD patients with eGFR 15–29 mL/min/1.73 m2.64,70,73,74 Remarkably, accumulating evidence shows that vegetable-based diets may rather have pleiotropic benefi cial eff ects for CKD patients (Figure 1).64
Figure 1. Pleiotropic benefi cial eff ects of a vegetable-based diet. This scheme
shows that a vegetable-based diet may yield multi-fold health benefi ts through a direct nutritional contribution and through changes in the instestinal microbiota. Adapted from “Vegetable-based diets for chronic kidney disease? It is time to reconsider” by Cases A, Nutrients 2019, 11, 1263.
Our fi ndings in this chapter are agreement with recent studies suggesting that patients with decreased kidney function may overall benefi t from higher consumption of fruits and vegetables rich in potassium.70,75,76 We provide the fi rst evidence to pave the way towards recommendations that support
VEGETABLE-BASED DIET
Vitamin K Short chain fatty acids
Butyrate Magnesium Phosphate Fiber & alkalization Intestinal transit Uremic toxins Inflammation & oxidation Beneficial products Improve microbiota
9
an overall survival benefi t of a relative increase of fruits and vegetables consumption post-kidney transplantation. We remark, however, that caution may still be needed with patients with eGFR <30 mL/min/1.73 m2, because for this particular patients, a potassium-restrictive diet is still suggested be the goal until pending data may support otherwise.73 Further investigation is warranted to guarantee the safety of a diet richer in fruits and vegetables in KTR, and to evaluate whether the benefi t of fruit and vegetable consumption has no upper limit as it is considered to be in the general population.77
In chapter 3 we aimed to investigate the potential inverse association of fi sh
intake with risk of cardiovascular and overall mortality in KTR. Fish are rich in the omega-3 polyunsaturated fatty acids (n-3 PUFA) EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which are nutrients which have been suggested to improve cardiovascular health.78–83 Proposed benefi cial health eff ects of marine-derived n-3 PUFA are wide-ranging, and may be favourably impacting infl ammation, fi brosis, lipid modulation, plaque stabilization, blood pressure, artery calcifi cation processes, and endothelial function.84–95 Each of these properties may separately and synergestically underlie, to a certain extent, the inverse association between marine-derived n-3 PUFA intake, or fi sh intake, and cardiovascular mortality risk observed in this cohort of Dutch KTR.
Our consistent fi ndings on the association of either n-3 PUFA or fi sh intake are relevant because current evidence derived from interventional studies based on isolated supplementation of EPA-DHA with the aim of decreasing risk of cardiovascular mortality in KTR is rather controversial or yet insuffi cient to validate its clinical uptake and prescription.96,97 Importantly, it should be realized that the relation between EPA-DHA intake and intermediate cardiovascular endpoints is the most steep within typical Western levels of intake (<750 mg/d EPA-DHA), with only very little additional benefi t reached by supplementary doses.87,88,98–107 With the exception of triglyceride-lowering eff ects, beyond typical dietary doses, EPA-DHA supplementation rather seems to reach a plateau on favourably eff ects on modulation of myocardial sodium and calcium ion channels, reducing susceptibility to ischemia-induced arrhythmia, reduced left ventricular workload and improved myocardial effi ciency as a result of reduced heart rate, lower systemic vascular resistance, and improved diastolic fi lling (Figure 2).87,88,98–107
Figure 2. Dose-response and time-course of the eff ects of EPA-DHA intake
on intermediate cardiovascular endpoints. This scheme shows that at typical Western levels of EPA-DHA intake, the observed dose-response relation is the steepest for most intermediate cardiovascular endpoints. Thereafter, upon supplementation, a subsequent plateau is generally observed, with exception of the dose-response relation on triglyceride-lowering eff ect. Potentially important eff ects on endothelial, autonomic, and infl ammatory responses are not shown because dose responses and time courses of such eff ects on clinical risk are not well established.108–110 Figure reprinted from “Fish Intake, Contaminants, and Human Health” by Mozaff arian D, JAMA 2006, 296, 1885−1889.
Fish is the main dietary source of EPA-DHA, and its consumption may provide EPA-DHA to cover the dose that favorably impacts cardiovascular risk the most. Its inclusion in diet of KTR seems reasonable because fi sh is a good source of protein without the accompanying ingestion of high amounts of saturated fat as is the case with fatty meat products. In our study population, KTR in the highest category of fi sh intake (≥15 g/day) had a median (interquartile range) intake of EPA-DHA [240 (170–334) mg/d], which is noticeably lower than the upper limit of dietary intake that yields the most benefi cial impact on cardiovascular risk. This observation may suggest that fi sh intake in Dutch KTR is relatively low, pointing towards to a large extent overlooked, cost-eff ective, and patient-centered risk management strategy to decrease cardiovascular mortality post-kidney transplant. Furthermore, these fi ndings underscore that prior to the implementation of any potential
9
supplementary strategy, recommendations may be aimed to reaching typical doses of EPA-DHA dietary intake. In this regard, it is fi rst important to know that the quantity of servings needed to reach a modest consumption of EPA-DHA (~250 mg per day on average) varies upon particular fi sh species. In agreement with most dietary guidelines, it is estimated that ~1-2 servings/ week of fatty (oily or dark meat) fi sh (e.g., anchovies, herring, salmon, sardines, trout, white tuna) provide enough EPA-DHA, while somewhat higher numbers of servings per week are recommended if lean (white meat) fi sh is consumed.111,112
Controversy arises, however, because dietary fi sh intake also represents the major source of human exposure to organic mercury.113–118 Indeed, in agreement with previous studies, we found that circulating mercury concentrations increased with greater fi sh consumption.119–121 Hereafter, in adults, the main concern is the potentially detrimental eff ect of chronic low-level mercury exposure — from modest fi sh consumption — on cardiovascular risk and outcomes.122 Both systemic (indirect) mechanisms and direct cardiovascular eff ects of mercury have been described.123–126 In this study of Dutch KTR, we observerd mercury concentrations comparable to, yet qualitatively lower than, previous reports within the European area and in the United States.127–129 We found no clear evidence for a counteracting eff ect by circulating mercury concentrations on the association between fi sh intake and the risks of cardiovascular and overall mortality. Yet, because observed circulating mercury values were within normal range (<5 μg/L), we cannot exclude the possibility that such counteracting eff ect could become perceptible over higher concentrations, or apparent by instead controlling for mercury levels in toenails or hair, which are biomarkers that may better provide an assessment of long-term mercury exposure.118,130,131 It should be realized, however, that while intermediate cardiovascular eff ects of mercury are suggestive, results on the impact on human cardiovascular disease are rather confl icting.132–136 In this regard, it should be noticed that fi sh is also rich in selenium, an essential trace element that may protect against both cardiovascular disease and toxic eff ects of mercury .137 The latter may potentially explain that coeffi cient estimates of the protective eff ect of fi sh intake were qualitatively better than those observed for n-3 PUFA intake alone. These data are in agreement with dietary guidelines supporting fi sh consumption as essential element of a healthy diet, with a potentially large public health impact from even small increases in fi sh consumption, and provides the fi rst observational
evidence to aid on the development of cautious approaches for the nutritional management of patients post-kidney transplantation.53
Overall, these fi ndings underscore that investigation of interventional strategies based on individualized recommendations to increase fruit, vegetable, and fi sh intake in KTR is warranted to substantiate these observational associations, and thus inform practice and policy.
Beyond fi sh and seafood-derived mercury pollution, cadmium is another environmental and lifestyle-related toxic contaminant that may theoretically be particularly hazardous in the post-kidney transplant setting, on the basis that in such long-term oxidative stress settings, cadmium-induced nephrotoxicity has been shown to associate with impaired kidney function at concentrations that are otherwise considered non-toxic.138–140 For the fi rst time in KTR, in
chapter 4 we provided data to suggest that nephrotoxic exposure to cadmium
represents an as yet overlooked hazard for preserved graft functioning. We demonstrated that higher plasma cadmium is independently and consistently associated with increased risk of late graft failure and kidney function decline in KTR. The study methods we used and further fi ndings we did warrant the following remarks.
First, it should be realized that the kidney proximal tubule, which is known to be the most aff ected by cadmium, is not reached by whole blood, but plasma ultra-fi ltrate. Our study is unique in relation to previous literature in that it analysed the likely most suitable sample — that is, all circulating cadmium except the type bound to erythrocytes — to study the potential impact of circulating cadmium as a proxy for exposure on endpoints of kidney function. Second, only 2 patients reached concentrations of plasma cadmium that are currently considered in the toxic range, yet even with these plasma cadmium distribution outliers excluded, we found a strong dose-response association with risk of late kidney graft failure. This fi nding is in agreement with the notion that cadmium is hazardous for kidney health ranging from even small levels of exposure, which highlights that bodily cadmium is a topic of clinical concern and may be in need of guidance to avoid exposure, appropriate monitoring and timely management.141–146 Third, providing pathophysiological support to the main fi nding, as well as interesting data for clinical outpatient follow-up of KTR, we showed that cadmium may be particularly hazardous in patients with abnormal liver enzyme levels. This observation is agreement with the understanding that once absorbed, cadmium is temporarily stored in the liver (bound to metallothionein). Thereafter, upon hepatocytes turnover,
cadmium-9
metallothionein is released into the circulation, fi ltered at the glomerulus, and reabsorbed at the proximal tubule, where it builds up with a half-life of up to 45 years.147 The latter, once again emphasizes the relevance of minimizing exposure to cadmium, which is indeed the most important therapeutic measure to prevent chronic toxicity. In this regard, and in agreement with previous literature, our fi ndings support that smoking is a signifi cant, yet modifi able, source of exposure to cadmium.
Whereas there is no specifi c therapy for cadmium-associated CKD, non-toxic cadmium-chelation may be feasible. Calcium ethylenediaminetetraacetic acid chelation of lead, which is a heavy metal with comparable nephrotoxicity to cadmium, has demostrated to slow progression of ESRD.148–150 Our fi ndings underscore that outpatient cadmium monitoring and cadmium-targeted interventional approaches may represent novel and meaningful risk-management strategies to decrease the burden of late kidney graft failure.
Part II — Infl ammation and Oxidative Stress & Vascular Calcifi cation
Traditional cardiovascular risk factors do not suffi ce to account for the excess cardiovascular risk of KTR. The long-standing interplay and feedback loop between infl ammation and oxidative stress — due to both residual kidney function loss and de novo transplant milieu-specifi c agents — provides a theoretical and conceptual framework upon which upcoming research may deepen the understanding of the pathophysiological status of KTR once they reach an otherwise stable clinical stage. Cutting-edge evidence on the potential hazard of novel (non-traditional) cardiovascular risk factors post-kidney transplant may aid on explaining excess cardiovascular risk, and potentially subsidize the development of novel therapeutic strategies.
In chapter 5, we fi rst approached the study of overall patients’ survival in
relation to vitamin C status. We measured plasma concentrations of the anti-infl ammatory and anti-oxidant agent vitamin C in stable KTR, and evaluated the prevalence of patients with plasma levels within the range of depletion (≤28 µmol/L or 0.5 mg/dL) in order to assess its potential association with risk of mortality. We found that vitamin C depletion was common (22%) in a stable outpatient population of KTR, and independently associated with an almost two-fold increased risk of overall mortality. In line, we observed an approximately 25% decreased risk of mortality per doubling of plasma vitamin C concentration. Because we were interested in exploring the potential underlying involvement of infl ammation, and to give pathophysiological
support to our fi ndings, we furthermore studied the potential mediation eff ect of predefi ned infl ammatory biomarkers, including high-sensitivity C-reactive protein, soluble intercellular cell adhesion molecule 1, and soluble vascular cell adhesion molecule 1. These biomarkers were used to compute a composite infl ammatory score to allow an overall characterisation of the infl ammatory status. This scoring procedure has the advantage of reducing the infl uence of measurement error and biological variability and avoids the problem of multiple testing in analyses performed with each biomarker separately.151–153 We found that this composite score of infl ammatory biomarkers approximately explained one-third of the association of vitamin C with mortality risk. These results support the notion that the benefi cial eff ect of vitamin C on patients’ survival occurs, at least to a considerable extent, through decreasing the chronic low-grade infl ammatory status of KTR, and underscore its sizeable relevance as novel risk factor for premature mortality post-kidney transplantation. In this regard, it should be realized that previous studies in haemodialysis patients have shown that vitamin C supplementation is eff ective in decreasing infl ammatory biomarkers.154,155 Whether such eff ect of vitamin C-based interventional strategies leads to an impact on long-term risk of mortality post-kidney transplant warrants further studies. It is important to remark that, to the best of our knowledge, previous studies (in diff erent clinical settings) have performed randomized supplementation of fi xed doses of vitamin C, despite initial vitamin C status. This is relevant because the therapeutical potential in non-depleted patients may be relatively low compared to patients with sub-physiological vitamin C status, and vitamin C defi cient patients may need even higher supplementation doses to reach physiological levels and make apparent the benefi ts from intervention. Although moderate doses of vitamin C supplementation (up to 1 g/d) are considered safe, the former point is relevant because vitamin C supplementation is not exempt of potential drawbacks such as oxalosis and toxicity, of which its appearance would largely depend on initial (pre-intervention) vitamin C status.156–158 While suggested vitamin C intake (40 mg/d for adults) can be obtained from a healthy diet, future investigations aimed to explore the potential of pharmacological interventions, are therefore suggested be designed to (i) take into account initial vitamin C status, (ii) consider individualized vitamin C supplementation, and (iii) monitor vitamin C status in order to adhere to reference values (28−85 µmol/L or 0.5−1.5 mg/ dL).159
9
and oxidative stress post-kidney transplantation, and to evaluate its postulated signifi cance as non-traditional factor partially explaining excess cardiovascular risk of KTR, in chapter 6 we measured circulating levels of two specifi c
oxidative stress biomarkers that —through known intracellular signalling pathways— lead to up-regulation of infl ammatory responses and amplify oxidative stress. The results of this study fi rstly support the epidemiological relevance of cardiovascular disease as leading cause of mortality in KTR, by showing that 52% of deaths that occurred during ~7 years of follow-up were due to cardiovascular causes.
Next, we consistently observed that per standard deviation relative increment of the oxidative stress biomarkers under study, i.e., Nԑ-(Carboxymethyl) lysine and Nԑ-(Carboxyethyl)lysine (advanced glycation endproducts, AGE), patients were at a clinically meaningful ~50% increased risk of cardiovascular mortality post-kidney transplant. Remarkably, these prospective associations were independent of eGFR, proteinuria and traditional cardiovascular risk factors such as body mass index, diabetes, blood pressure and smoking status. Furthermore, we found that free thiol groups and soluble vascular cell adhesion molecule-1 consistently explained ~35% of the association between higher levels of AGE and increased risk of cardiovascular mortality. Our results may support the hypothesis that —upon binding to specifi c cellular receptors— AGE may up-regulate downstream biomarkers of infl ammation and oxidative stress. These fi ndings support the notion that infl ammation and endothelial dysfunction are redox-sensitive responses, and that intracellular pathways involving activation of transcription factors ultimately feed the loop between oxidative stress and infl ammatory responses, contributing to excess cardiovascular risk post-kidney transplant.
Dietary AGE content is also an important contributor to AGE accumulation in CKD patients. Future investigations are warranted to evaluate whether interventions aimed at decreasing exogenous dietary sources of AGE may decrease oxidative stress and infl ammation, and represent safe and cost-eff ective cardiovascular risk-management strategies.160–162 Furthermore, with diverse pharmacological agents aimed at inhibiting the formation of AGE, and with novel AGE breakers increasingly becoming available,163 these fi ndings highlight the need of performing external validation of our results in diff erent and larger populations of KTR to further support exploration of potential novel avenues of AGE-targeted interventions to decrease the burden of premature cardiovascular mortality in KTR.
Infl ammation also plays a cornerstone signalling role linking challenges of both immune and non-immune nature with interstitial fi brosis and tubular atrophy, which represents a common pathological pathway to mechanisms leading to kidney injury.33,34,43,164–166 This concept came to set out the basis for the hypothesis that structural damage and detrimental function of the kidney are the cumulative consequence of a variety of hazards associated with up-regulation of infl ammatory status and pro-oxidant responses as shared response.33,34,43,166 In chapter 7 we studied galectin-3, which is a
β-galactoside-binding lectin and novel biomarker of acute and chronic
low-grade infl ammation, previously shown to be involved in mechanisms leading to kidney fi brosis, and most recently linked with increased risk of incident CKD. For the fi rst time, our study shows that galectin-3 levels are remarkably high in KTR, and independently associated with increased risk of graft failure over ~10-years of follow-up, with particularly strong associations among KTR with smoking history or with high systolic blood pressure. The observed interaction with blood pressure is consistent with fi ndings of previous studies in the general population, and may further support the involvement of galectin-3 in postulated novel mechanisms of cardiac-renal interactions. These results complement previous studies on the association of galectin-3 with incident CKD, by extending those to a specifi c high-risk population of progressive loss of kidney function.167,168
Because galectin-3 has been consistently implicated in the development of fi brosis resulting from infl ammatory or toxic insults, it seems compelling to speculate that galectin-3−targeted pharmacological strategies may provide a therapeutic alternative to downturn the deleterious eff ect of a broad variety of hazards associated with kidney fi brosis and function loss. Such interventional strategies may a priori seem particularly promising in the post-kidney transplant clinical setting. Our fi ndings point towards yet-to-unfold opportunities to aid on non-invasive, early and individualized long-term clinical follow-up post-kidney transplant. Prior to the formal proposal of therapeutic potential, however, further investigations on the evolving and broad profi le of homeostatic and pathophysiological bioactivities of galectin-3 are warranted.169
Beyond infl ammation, a recent elegant study supports the hypothesis that decline of cardiovascular risk post-kidney transplant partly depends on the resolution of chronic kidney disease-mineral and bone disorders (CKD-MBD).23 Within the context of CKD-MBD, vascular calcifi cation
9
— a currently established cardiovascular risk factor in KTR, as shown in a previous study from our group and studies of others 170–175 — is linked with bone disease due to inter-related pathophysiological mechanisms, setting out the basis for a bone-vascular axis hypothesis. Because disturbed bone and mineral metabolism persists after kidney transplantation, and because maintenance immunosuppressive therapy adds a transplant-specifi c hazard for
bone disease, in chapter 8 we hypothesized that bone mineral density (BMD)
is independently and inversely associated with risk of vascular calcifi cation in KTR.12,36,176 Recommendations for BMD testing after transplantation by means of dual-energy X-ray absorptiometry (DXA) have been formally incorporated
in the KDIGO 2017 clinical practice guidelines. This imaging technique also allows assessment of abdominal aortic calcifi cation (AAC) with a low radiation burden.177 Therefore, in this study we expanded the clinical accountability of a DXA scan, by showing that BMD disorders according to DXA scan data are highly prevalent in KTR (54%), and also showing its independent association with increased risk of AAC, thus providing data in favor of the bone-vascular axis hypothesis in KTR. Because DXA scans are non-invasive, relatively
accurate and cost-eff ective, these results underscore the notion that DXA scan
is an interesting imaging method for screening of bone mass and vascular calcifi cation early post-kidney transplant.177
Because kidney transplantation aims to restore kidney function but incompletely mitigates collateral mechanisms of disease, such as chronic low-grade infl ammation with persistent redox imbalance, and deregulated mineral and bone metabolism, the second part of this thesis investigated specifi c laboratory and clinical readouts with a proposed involvement in such pathological pathways. First, by using the theoretical and conceptual framework of the interplay between infl ammation and oxidative stress, we deepened the understanding of the pathophysiological status of KTR once they reach an otherwise stable clinical stage. We were able to assess the contribution of this phenomenon to excess risk of cardiovascular mortality and late kidney graft failure, and point towards potential interventional strategies. Finally, we provided evidence that may support the existence of a bone-vascular axis post-kidney transplant. Future studies are warranted to evaluate whether incorporation of BMD and vascular calcifi cation assessment by means of a DXA scan within the context of outpatient follow-up, may aid on the evaluation and guidance of therapeutic management of CKD-MBD and cardiovascular risk post-kidney transplant.
DISCUSSION AND FUTURE PERSPECTIVES
K
idney transplantation is the preferred treatment for ESRD. In a few decades, advances in immunosuppressive therapy, tissue typing, treatment of infections and surgical techniques led kidney transplantation to evolve from an exotic therapeutic option to gold-standard care.178 It is known, however, that over recent years, advances in kidney transplantation have been mainly driven by improvements on fi rst-year graft and patient survival.179 Several challenges remain to be addressed in order to decrease the excessive load of disease post-kidney transplant, and thus ultimately contribute to a longer life-span of kidney transplant recipients (KTR). Future progress in the fi eld of kidney transplantation is expected from amelioration of excess cardiovascular risk and the long-standing burden of late graft failure.179 This thesis assessed traditional — yet rather overlooked — risk factors post-kidney transplant, and investigated novel (non-traditional) risk factors along the theoretical and conceptual framework in which kidney transplantation aims to restore kidney function but imcompletely mitigates mechanisms of disease, which are furthermore perpetuated by the kidney transplantation milieu, ultimately challenging the improvement of long-term outcomes post-kidney transplant. This approach allowed us to underscore potentially modifi able factors, which are suggestive of early, cost-eff ective and patient-centered interventional strategies, and refl ect on future prospects in the fi eld from several perspectives. From an epidemiological view, we were able to unravel prevailing — yet mostly overlooked — preventive opportunities with a meaningful potential for application at a general clinical level. The inverse associations between fruit, vegetable and fi sh intake with risk of cardiovascular and overall mortality post-kidney transplantation, point towards promising early risk-management strategies based on practical and cost-eff ective measures tackling the major cause of premature death with a functioning graft, i.e., cardiovascular mortality. In theory, dietary intervention strategies based on personalized recommendations to increase fruit, vegetable, and fi sh intake in KTR may yield a meaningful reduction of cardiovascular risk. To the best of our knowledge no clinical trial has been devoted to investigating this hypothesis, despite the fact that the benefi cial eff ect of adequate nutritional control in any chronic disease is universally accepted, and that it is well-recognized that KTR are patients at particularly high cardiovascular risk. Strinkingly, currently there is absence of shared agreements on important nutritional aspects post-kidney9
transplantation. Indeed, KTR want to hear information on dietary guidelines, because they want to increase their knowledge to have the opportunity to adequately manage their diets and health.6,180 Of note, in general kidney disease patients rank dietary research among their priorities.181 At diff erence, clinicians in general consider nutrition of KTR just an additional element of the care planning, which may be refl ected by, or due to, the lack of evidence-based recommendations.6 Of course, a biased research agenda can have several consequences.182 As in other research areas with a mismatch between the amount of published work on diff erent interventions and the degree of interest of consumers or burden of disease, dietary advise and nutritional management of KTR seems to remain an underrepresented problem in the research agenda of the kidney transplantation research community.181–183 Considering our fi ndings, investigation of potential interventional strategies based on individualized recommendations to increase fruit, vegetable, and fi sh intake in KTR is warranted in order to substantiate our observational associations, and thus pave the way to inform practice and policy.
Likewise, although heavy metals are environmental toxins with epidemiological relevance and a demonstrated etiological role on the incidence and progression of CKD, their toxicity continues to receive little to null research priority, which is particularly the case post-kidney transplantation. Available evidence supports the notion that heavy metals are hazardous for kidney health in a dose-dependent fashion, ranging from even small levels of contamination to overt toxicity.141–146 These data are consistent with our fi ndings on the association of plasma cadmium with risk of kidney function decline and late kidney graft failure. In our study, cadmium showed a dose-dependent association with graft failure events over increasing tertiles of plasma concentration, which suggests that this is not a matter to be adressed exclusively in highly contaminated regions, but rather a topic of concern over areas with various degrees of cadmium pollution. For the particular case of Europe, it should be taken into account that environmental cadmium pollution during the past century may have caused a fi fty-fold rise in its concentration in the human renal cortex, wherein it accumulates 50% more than in the total kidney, with a half-life of up to 45 years.147,184 In The Netherlands and Belgium, moreover, environmental cadmium contamination is of exceptional relevance compared to other countries of the European Union (EU).144,185–187 In The Netherlands, the most important origin is transboundary through upstream countries’ accumulating pollution in Dutch sediments and surface water due
to the delta situation of the country. A high cadmium-containing landfi ll and a large percentage of incinerated household waste may also explain why the cadmium pollution situation in The Netherlands is a special case, being worse than the average EU.186,187 We suggest that future research be conducted to investigate potentially signifi cant health impact of environmental exposure to cadmium in The Netherlands, with a special focus on longitudinal estimates of kidney accumulation, structural damage, and impaired function, including but not restricted to the particular population of KTR, and potentially also broadly over the general population. Similar recommendations apply to other countries of the EU, and also to other regions of the world wherein heavy metals — particularly cadmium — are strong risk factor candidates to at least partly explain CKD of Uncertain Etiology (CKDu), which currently is a main research goal of the World Health Organisation and the International Society of Nephrology to develop appropriate health policy and public health responses to this issue.141,146,188–196 Next, because cadmium reduces insulin levels and has direct cytotoxic eff ects on the pancreas, liver, adipose tissue and adrenal gland, we also warrant future studies to investigate whether cadmium may synergestically damage the kidney through direct nephrotoxicity and hyperglycemia.146,192,197–211 Finally, considering the relevance of abnormal bone mineral density post-kidney transplantation, and reports of previous studies on the association of cadmium exposure with risk of osteoporosis and fracture, future investigations of cadmium in KTR are warranted to evaluate the potential contribution of cadmium exposure to increased risk of abnormal bone mineral density.212–220
At a pathophysiological level we were able to investigate the phenomenon of chronic infl ammation with persistent redox imbalance, and provide evidence of the existance of a bone-vascular axis post-kidney transplantation. We propose that these two major mechanisms of disease are imcompletely mitigated post-kidney transplantation and may ultimately challenge the improvement of outcomes beyond the fi rst-year post-kidney transplantation and beyond hazards of purely immunological nature. Our data may support the hypothesis that infl ammation and oxidative stress, deregulated bone and mineral metabolism, and cardiovascular disease participate in a self-perpetuating cycle, which, if not interrupted, can lead to progressive cardiovascular disease and kidney dysfunction.221 These insiduous and rather asymptomatic pathophysiological processes seem to occurr over an extended period, from a wide varying time pre-transplantation, further perpetuated and
9
even promoted within the transplant milieu. Exceedingly high prevalence of cardiovascular disease, precipitated derangements of metabolism as well as high risk of malignancies resemble the general aging process, however, at a particularly accelerated pace in these patients. This consideration may be related to the observation that life-span of KTR has not been positively impacted in parallel with improvements of short-term outcomes, perhaps because advances in immunosuppression, tissue typing, treatment of infections, surgical techniques nor partial recovery of kidney function itself have completely mitigated the aforementioned collateral mechanisms of disease. By characterizing non-traditional risk factors, relevant clinical readouts, and specifi c signalling agents, this thesis may support the interplay between infl ammation and oxidative stress, and deregulated mineral and bone metabolism, as pathways of injury that remain active in seemingly stable KTR and adversely impact long-term outomes post-kidney transplantation.
Overall, this thesis may support and acknowledge the need of providing a systematic assessment of the impact of traditional risk factors in the specfi c post-kidney transplant setting, as well as identifying novel and potentially modifi able risk factors potentially explaining excess risk of adverse long-term outcomes in outpatient KTR. On this understanding, our group designed and is currently executing the long-lasting prospective cohort study and biobank of solid organ transplant recipients “TransplantLines”. The general aim of this study is to provide longitudinal data to evaluate the impact of the transplantation milieu on a broad variety of health parameters, and thus generate evidence-based hypotheses for individualized early risk-management strategies to advance survival rates of the transplanted kidney, organ recipient and quality of life after transplantation. Five pillars of data collection (i.e., clinical data, physical tests, cognitive tests, questionnaires, and biomaterials, as depicted in Figure 3) will allow extensive phenotyping of KTR before,
during transplantation and at follow-up visits over several years. This multi-fold approach of data collection covering several specialized fi elds of health care underlines the multidisciplinary eff orts needed to comprehensively improve the long-term burden of disease, reduced life-span and impaired quality of life post-kidney transplantation, while at the same time keeping in the center of care each patient in an holistic fashion, and aligning research team’s agenda with the needs of the population it is meant to serve.182,222
Figure 3. Five pillars of data collection and biobanking of TransplantLines.
This fi gure illustrates the multi-fold approach for data collection and biobanking of solid organ transplant recipients, while emphasizing the key centred-role of patients in research and healthcare eff orts.
Furhermore, we specially remark on our most recent and ongoing study TransplantLines-Coronary Artery Calcifi cation (CAC), which aims to extend the biobanking eff orts by providing imaging examinations and thorough assessment of laboratory parameters specifi cally aiding to provide an early and non-invasive evaluation of the vascular calcifi cation phenomenon post-kidney transplant, as fi rst step to develop interventions to slow down or arrest the progression of vascular calcifi cation in KTR.
9
a global research-in-human health point of view may be speculated. The prevalence of CKD worldwide has steadily increased over recent decades, in parallel with an ever longer population’s life-span, representing an unquestionable global public priority.223 CKD is an independent risk factor for cardiovascular disease, of which the risk has also increased in parallel with longer life expectancy. Cardiovascular disease, moreover, importantly adds to the worldwide burden of disease, underscoring that the mechanisms of cross-talk between kidney disease and cardiovascular disease will also escalate in relevance in the near future. In a population characterized by premature death, this thesis provides interesting data highlighting the self-perpetuating cycle between CKD, infl ammation with persisting redox imbalance, and deregulated bone and mineral metabolism, and cardiovascular disease, which is thought to then further promote loss of kidney function. Previous studies, argue that —over varying genetic setting— the persistence over time of infl ammatory responses to immune and other stressing stimuli are of importance, and provide a biologic background favouring susceptibility to age-related chronic diseases, such as cardiovascular disease, cancer, CKD, osteoporosis and diabetes, with detrimental eff ects that ultimate adversely aff ect life-span.224 Future research aimed at investigating the inter-play between CKD, cardiovascular disease and other major chronic diseases, particularly within the context of elderly populations, may be suggested to be based on the theoretical and conceptual framework of infl ammation and oxidative stress, also known as infl amm-aging.224
CONCLUSION
In the clinical setting of KTR after the fi rst-year post-transplant, in this thesis we studied and characterized the clinical impact of (i) traditional and potentially modifi able —yet rather overlooked— risk factors, such as lifestyle, diet and exposure to toxic contaminants, which are underexplored areas in the kidney transplantation fi eld. This approach unfolded potentially cost-eff ective and patient-centred opportunities that may increase the life-span of KTR once they reach an otherwise stable clinical stage. Dietary interventional strategies based on individualized recommendations to increase fruit, vegetable, and fi sh intake in KTR may substantially alleviate the burden of premature death among outpatient KTR. Investigation of the potential impact of policy measures and clinical guidance to decrease the exposure to cadmium and other toxic environmental contaminants is also warranted. Against the background that kidney transplantation aims to restore kidney function but incompletely mitigates collateral mechanisms of disease, this thesis may support the notion that non-traditional risk factors, such as chronic low-grade infl ammation with persistent redox imbalance, and deregulated mineral and bone metabolism, may at least partly explain the excess risk of premature death of KTR. Further research on these non-traditional risk factors is also warranted as it may pave the way towards decreasing the long-standing burden of premature death post-kidney transplantation.
9
REFERENCES
1. Fry K, Patwardhan A, Ryan C, et al. Development of evidence-based guidelines for
the nutritional management of adult kidney transplant recipients. J Ren Nutr 2009, 19, 101–104.
2. Cochran CC, Kent PS. Nutrition management of the adult renal transplant patient. A
clinical guide to nutrition care in kidney disease. 3rd ed. Chicago IL: American Diabetic Association, 2004.
3. Zelle DM, Kok T, Dontje ML et al. The role of diet and physical activity in
post-transplant weight gain after renal post-transplantation. Clin Transplant 2013, 27, E484– E490.
4. Nolte Fong J V, Moore LW. Nutrition trends in kidney transplant recipients: the
importance of dietary monitoring and need for evidence-based recommendations. Front
Med 2018, 5, 302.
5. Klaassen G, Zelle DM, Navis GJ, et al. Lifestyle intervention to improve quality of
life and prevent weight gain after renal transplantation: Design of the Active Care after Transplantation (ACT) randomized controlled trial. BMC Nephrology 2017, 18, 296.
6. Sabbatini M, Ferreri L, Pisani A, et al. Nutritional management in renal transplant
recipients: A transplant team opportunity to improve graft survival. Nutr Metab
Cardiovasc Dis 2019, 29, 319–324.
7. Vazquez MA, Jeyarajah DR, Kielar ML, et al. Long-term outcomes of renal
transplantation: A result of the original endowment of the donor kidney and the infl ammatory response to both alloantigens and injury. Curr Opin Nephrol Hypertens 2000, 9, 643–648.
8. Winkelmayer WC, Lorenz M, Kramar R, et al. C-reactive protein and body mass index
independently predict mortality in kidney transplant recipients. Am J Transplant 2004, 4, 1148–1154.
9. Sezer S, Akcay A, Ozdemir FN, et al. Post-transplant C-reactive protein monitoring can
predict chronic allograft nephropathy. Clin Transplant 2004, 18, 722–725.
10. Abedini S, Holme I, März W, et al. Infl ammation in renal transplantation. Clin J Am Soc
Nephrol 2009, 4, 1246–1254.
11. van Ree RM. Chronic low-grade infl ammation in renal transplantation. University
Library Groningen, 2009.
12. Dahle DO, Mjøen G, Oqvist B, et al. Infl ammation-associated graft loss in renal
transplant recipients. Nephrol Dial Transplant 2011, 26, 3756–3761.
13. Yilmaz MI, Sonmez A, Saglam M, et al. A longitudinal study of infl ammation,
CKD-mineral bone disorder, and carotid atherosclerosis after renal transplantation. Clin J Am
Soc Nephrol 2015, 10, 471–479.
14. Cerrillos-Gutiérrez JI, Miranda-Díaz AG, Preciado-Rojas P, et al. The benefi cial eff ects
of renal transplantation on altered oxidative status of esrd patients. Oxid Med Cell
Longev 2016, 2016, 1–6.
15. Molnar MZ, Nagy K, Remport A et al. Infl ammatory markers and outcomes in kidney
16. Gennip ACE van, Broers NJH, ter Meulen KJ, et al. Endothelial dysfunction and low-grade infl ammation in the transition to renal replacement therapy. PLoS One 2019, 14, e0222547.
17. Kalantar-Zadeh K, Molnar MZ, Kovesdy CP, et al. Management of mineral and bone
disorder after kidney transplantation. Curr Opin Nephrol Hypertens 2012, 21, 389–403.
18. Egbuna OI, Taylor JG, Bushinsky DA, et al. Elevated calcium phosphate product after
renal transplantation is a risk factor for graft failure. Clin Transplant 2007, 21, 558– 566.
19. Evenepoel P, Claes K, Kuypers D, et al. Natural history of parathyroid function and
calcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial
Transplant 2004, 19, 1281–1287.
20. Monier-Faugere M-C, Mawad H, Qi Q, et al. High prevalence of low bone turnover and
occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000, 11, 1093-1099.
21. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and
management. Ann Intern Med 1990, 112, 352–364.
22. Lou I, Foley D, Odorico SK, et al. How well does renal transplantation cure
hyperparathyroidism? Ann Surg 2015, 262, 653–659.
23. Wolf M, Weir MR, Kopyt N, et al. A prospective cohort study of mineral metabolism
after kidney transplantation. Transplantation 2016, 100, 184–193.
24. Evenepoel P, Lerut E, Naesens M, et al. Localization, etiology and impact of calcium
phosphate deposits in renal allografts. Am J Transplant 2009, 9, 2470–2478.
25. Mazzaferro S, Pasquali M, Taggi F, et al. Progression of coronary artery calcifi cation in
renal transplantation and the role of secondary hyperparathyroidism and infl ammation.
Clin J Am Soc Nephrol 2009, 4, 685–690.
26. Sprague SM, Belozeroff V, Danese MD, et al. Abnormal bone and mineral metabolism
in kidney transplant patients--a review. Am J Nephrol 2008, 28, 246–253.
27. Julian BA, Laskow DA, Dubovsky J, et al. Rapid loss of vertebral mineral density after
renal transplantation. N Engl J Med 1991, 325, 544–550.
28. Kaysen GA. The microinfl ammatory state in uremia: causes and potential consequences.
J Am Soc Nephrol 2001, 12, 1549–1557.
29. Iyer SP, Nikkel LE, Nishiyama KK, et al. Kidney transplantation with early
corticosteroid withdrawal: paradoxical eff ects at the central and peripheral skeleton. J
Am Soc Nephrol 2014, 25, 1331–1341.
30. Grotz WH, Mundinger FA, Gugel B, et al. Bone mineral density after kidney
transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation. Transplantation 1995, 59, 982–986.
31. Aroldi A, Tarantino A, Montagnino G, et al. Eff ects of three immunosuppressive
regimens on vertebral bone density in renal transplant recipients. Transplantation 1997, 63, 380–386.
32. Rush DN, Jeff ery JR, Gough J. Sequential protocol biopsies in renal transplant patients.
Clinico-pathological correlations using the Banff schema. Transplantation 1995, 59, 511–514.
9
33. Rush DN, Karpinski ME, Nickerson P, et al. Does subclinical rejection contribute to
chronic rejection in renal transplant patients? Clin Transplant 1999, 13, 441–446.
34. Nankivell BJ, Borrows RJ, Fung CL-S, et al. The natural history of chronic allograft
nephropathy. N Engl J Med 2003, 349, 2326–2333.
35. Beveridge T, Calne RY. Cyclosporine (Sandimmun) in cadaveric renal transplantation.
Ten-year follow-up of a multicenter trial. European Multicentre Trial Group.
Transplantation 1995, 59, 1568–1570.
36. Remuzzi G, Perico N. Cyclosporine-induced renal dysfunction in experimental animals
and humans. Kidney Int Suppl 1995, 52, S70-S74.
37. Myers BD, Newton L. Cyclosporine-induced chronic nephropathy: an obliterative
microvascular renal injury. J Am Soc Nephrol 1991, 2, S45-S52.
38. Bertani T, Ferrazzi P, Schieppati A, et al. Nature and extent of glomerular injury induced
by cyclosporine in heart transplant patients. Kidney Int 1991, 40, 243–250.
39. Solez K, Vincenti F, Filo RS. Histopathologic fi ndings from 2-year protocol biopsies
from a US multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. Transplantation 1998, 66, 1736–1740.
40. Davies DR, Bittmann I, Pardo J, et al. Histopathology of calcineurin inhibitor-induced
nephrotoxicity. Transplantation 2000, 69, SS11-3.
41. Nankivell BJ, Borrows RJ, Fung CL-S, et al. Natural history, risk factors, and impact of
subclinical rejection in kidney transplantation. Transplantation 2004, 78, 242–249.
42. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future
directions. Transplantation 2006, 81, 643–654.
43. Benigni A, Bruzzi I, Mister M, et al. Nature and mediators of renal lesions in kidney
transplant patients given cyclosporine for more than one year. Kidney Int 1999, 55, 674–685.
44. Cozzolino M, Mangano M, Stucchi A, et al. Cardiovascular disease in dialysis patients.
Nephrol Dial Transplant 2018, 33, iii28–iii34.
45. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet 1994, 344, 793–795.
46. Gillman MW, Cupples LA, Gagnon D, et al. Protective eff ect of fruits and vegetables
on development of stroke in men. JAMA 1995, 273, 1113.
47. Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk
of ischemic stroke. JAMA 1999, 282, 1233–1239.
48. Bazzano LA, He J, Ogden LG, et al. Fruit and vegetable intake and risk of cardiovascular
disease in US adults: the fi rst National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Am J Clin Nutr 2002, 76, 93–99.
49. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke:
meta-analysis of cohort studies. Lancet 2006, 367, 320–326.
50. Dauchet L, Amouyel P, Hercberg S, et al. Fruit and vegetable consumption and risk of
coronary heart disease: a meta-analysis of cohort studies. J Nutr 2006, 136, 2588–2593.
51. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defi ning and setting national goals for
cardiovascular health promotion and disease reduction: The american heart association’s strategic impact goal through 2020 and beyond. Circulation 2010, 121, 586–613.
52. Crowe FL, Roddam AW, Key TJ, et al. Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. Eur Heart J 2011, 32, 1235–1243.
53. Zhang X, Shu X-O, Xiang Y-B, et al. Cruciferous vegetable consumption is associated
with a reduced risk of total and cardiovascular disease mortality. Am J Clin Nutr 2011, 94, 240–246.
54. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease
and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990– 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012, 380, 2224–2260.
55. Larsson SC, Virtamo J, Wolk A. Total and specifi c fruit and vegetable consumption and
risk of stroke: A prospective study. Atherosclerosis 2013, 227, 147–152.
56. Hu D, Huang J, Wang Y, et al. Fruits and vegetables consumption and risk of stroke: a
meta-analysis of prospective cohort studies. Stroke 2014, 45, 1613–1619.
57. Wang X, Ouyang Y, Liu J, et al. Fruit and vegetable consumption and mortality from all
causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ 2014, 349, g4490.
58. US Department of Health and Human Services and US Department of Agriculture
(2015). 2015–2020 Dietary Guidelines for Americans. 8th Edition.
59. Du H, Li L, Bennett D, et al. Fresh fruit consumption and major cardiovascular disease
in China. N Engl J Med 2016, 374, 1332–1343.
60. Forouzanfar MH, Alexander L, Anderson HR, et al. Global, regional, and national
comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013, a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386, 2287–2323.
61. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular
disease prevention in clinical practice. Eur Heart J 2016, 37, 2315–2381.
62. Aune D, Giovannucci E, Boff etta P, et al. Fruit and vegetable intake and the risk of
cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies. Int J Epidemiol 2017, 46, 1029– 1056.
63. Zhan J, Liu Y-J, Cai L-B, et al. Fruit and vegetable consumption and risk of
cardiovascular disease: a meta-analysis of prospective cohort studies. Crit Rev Food
Sci Nutr 2017, 57, 1650–1663.
64. Cases A, Cigarrán-Guldrís S, Mas S, et al. Vegetable-based diets for chronic kidney
disease? it is time to reconsider. Nutrients 2019, 11, 1263.
65. Allon M. Hyperkalemia in end-stage renal disease: mechanisms and management. J Am
Soc Nephrol 1995, 6, 1134–1142.
66. Weiner ID, Wingo CS. Hyperkalemia, a potential silent killer. J Am Soc Nephrol 1998,
9, 1535–1543.
67. Sarafi dis PA, Blacklock R, Wood E et al. Prevalence and factors associated with
hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc
9
68. Barsotti G, Morelli E, Cupisti A, et al. A low-nitrogen low-phosphorus vegan diet for
patients with chronic renal failure? Nephron 1996, 74, 390–394.
69. Soroka N, Silverberg DS, Greemland M, et al. Comparison of a vegetable-based (soya)
and an animal-based low-protein diet in predialysis chronic penal failure patients.
Nephron 1998, 79, 173–180.
70. Goraya N, Simoni J, Jo CH, et al. A comparison of treating metabolic acidosis in CKD
stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate.
Clin J Am Soc Nephrol 2013, 8, 371–381.
71. Goraya N, Simoni J, Jo C-H, et al. Treatment of metabolic acidosis in patients with
stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular fi ltration rate. Kidney Int 2014, 86, 1031–1038.
72. Joshi S, Shah S, Kalantar-Zadeh K. Adequacy of plant-based proteins in chronic kidney
disease. J Ren Nutr 2019, 29, 112–117.
73. Clegg DJ, Hill Gallant KM. Plant-based diets in CKD. Clin J Am Soc Nephrol 2019, 14,
141–143.
74. St-Jules DE, Goldfarb DS, Sevick MA. Nutrient non-equivalence: does restricting
high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients? J
Ren Nutr 2016, 26, 282–287.
75. Goraya N, Simoni J, Jo C, et al. Dietary acid reduction with fruits and vegetables or
bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular fi ltration rate due to hypertensive nephropathy. Kidney Int 2012, 81, 86–93.
76. Tyson CC, Lin PH, Corsino L, et al. Short-term eff ects of the DASH diet in adults
with moderate chronic kidney disease: A pilot feeding study. Clin Kidney J 2016, 9, 592–598.
77. European Heart Network. Diet, physical activity and cardiovascular disease prevention
in Europe. Brussels, Belguim: European Heart Network, 2011.
78. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between
fi sh consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985, 312, 1205–1209.
79. Kromhout D, Feskens EJ, Bowles CH. The protective eff ect of a small amount of fi sh
on coronary heart disease mortality in an elderly population. Int J Epidemiol 1995, 24, 340–345.
80. Stone NJ. Fish consumption, fi sh oil, lipids, and coronary heart disease. Circulation
1996, 94, 2337–2340.
81. Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: revision 2000: A
statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 2000, 102, 2284–2299.
82. Psota TL, Gebauer SK, Kris-Etherton P. Dietary omega-3 fatty acid intake and
cardiovascular risk. Am J Cardiol 2006, 98, 3–18.
83. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fi sh or fi sh-oil supplements,
but not α-linolenic acid, benefi t cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006, 84, 5–17.
84. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease— fi shing for a natural treatment. BMJ 2004, 328, 30.
85. Thies F, Garry JMC, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with
stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003, 361, 477–485.
86. Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressure response to fi sh oil
supplementation: Metaregression analysis of randomized trials. J Hypertens 2002, 20, 1493–1499.
87. Sekikawa A, Miura K, Lee S, et al. Long chain n-3 polyunsaturated fatty acids and
incidence rate of coronary artery calcifi cation in Japanese men in Japan and white men in the USA: population based prospective cohort study. Heart 2014, 100, 569–573.
88. Eritsland J, Arnesen H, Seljefl ot I, et al. Long-term eff ects of n-3 polyunsaturated fatty
acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul Fibrinolysis 1995, 6, 17–22.
89. Von Schacky C, Angerer P, Kothny W, et al. The eff ect of dietary ω-3 fatty acids on
coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann
Intern Med 1999, 130, 554–562.
90. Wang Q, Liang X, Wang L, et al. Eff ect of omega-3 fatty acids supplementation on
endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis 2012, 221, 536–543.
91. Christensen JH. Omega-3 polyunsaturated fatty acids and heart rate variability. Front
Physiol 2011, 2, 84.
92. Masson S, Marchioli R, Mozaff arian D, et al. Plasma n-3 polyunsaturated fatty acids in
chronic heart failure in the GISSI-heart failure trial: relation with fi sh intake, circulating biomarkers, and mortality. Am Heart J 2013, 165, 208–215.
93. Calder PC. n-3 polyunsaturated fatty acids, infl ammation, and infl ammatory diseases.
Am J Clin Nutr 2006, 83, 1505S–1519S.
94. Calder PC. Omega-3 fatty acids and infl ammatory processes. Nutrients 2010, 2, 355–
374.
95. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997,
65, 1645S-1654S.
96. Tatsioni A, Chung M, Sun Y, et al. Eff ects of fi sh oil supplementation on kidney
transplantation: a systematic review and meta-analysis of randomized, controlled trials.
J Am Soc Nephrol 2005, 16, 2462–2470.
97. Lim AK, Manley KJ, Roberts MA, et al. Fish oil for kidney transplant recipients.
Cochrane Database Syst Rev 2016, (8), CD005282.
98. Mozaff arian D, Rimm EB. Fish intake, contaminants, and human health. JAMA 2006,
296, 1885.
99. McLennan PL. Myocardial membrane fatty acids and the antiarrhythmic actions of
dietary fi sh oil in animal models. Lipids 2001, 36, S111–S114.
100. Leaf A, Kang JX, Xiao YF, et al. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fi sh oils. Circulation 2003, 107, 2646–2652.
9
101. Mozaff arian D, Geelen A, Brouwer IA, et al. Eff ect of fi sh oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation 2005, 112, 1945–1952. 102. Mozaff arian D, Gottdiener JS, Siscovick DS. Intake of tuna or other broiled or baked
fi sh versus fried fi sh and cardiac structure, function, and hemodynamics. Am J Cardiol 2006, 97, 216–222.
103. Dallongeville J, Yarnell J, Ducimetière P, et al. Fish consumption is associated with lower heart rates. Circulation 2003, 108, 820–825.
104. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97, 1837–1847.
105. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998, 81, 7B-12B.
106. Jouven X, Zureik M, Desnos M, et al. Resting heart rate as a predictive risk factor for sudden death in middle-aged men. Cardiovasc Res 2001, 50, 373–378.
107. Kannel WB, Kannel C, Paff enbarger RS, et al. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987, 113, 1489–1494.
108. Nestel PJ. Fish oil and cardiovascular disease: lipids and arterial function. Am J Clin
Nutr 2000, 71, 228S-31S.
109. Mori TA, Beilin LJ. Omega-3 fatty acids and infl ammation. Curr Atheroscler Rep 2004, 6, 461–467.
110. Christensen JH. n-3 fatty acids and the risk of sudden cardiac death. Emphasis on heart rate variability. Dan Med Bull 2003, 50, 347–367.
111. Oomen CM, Feskens EJM, Räsänen L, et al. Fish consumption and coronary heart disease mortality in Finland, Italy, and the Netherlands. Am J Epidemiol 2000, 151, 999–1006.
112. Mozaff arian D, Lemaitre RN, Kuller LH, et al. Cardiac benefi ts of fi sh consumption may depend on the type of fi sh meal consumed: The cardiovascular health study.
Circulation 2003, 107, 1372–1377.
113. World Health Organization. Preventing disease through healthy environments: exposure to cadmium: a major public health concern. Geneva: World Health Organization, 2019. 114. World Health Organization. Water, Sanitation and Health Team. Mercury in health care:
policy paper. Geneva: World Health Organization, 2005.
115. National Research Council (US) Committee on the Toxicological Eff ects of Methylmercury. Toxicological eff ects of methylmercury. Washington DC: National Academies Press, 2000.
116. US Environmental Protection Agency. Mercury Study for Congress. Volume I: Executive summary. US Environmental Protection Agency, Offi ce of Air Quality Planning and Standards and Offi ce of Research and Development, 1997.
117. Hightower JM, Moore D. Mercury levels in high-end consumers of fi sh. Environ Health
Perspect 2003, 111, 604–608.
118. Joshi A, Douglass CW, Kim HD, et al. The relationship between amalgam restorations and mercury levels in male dentists and nondental health professionals. J Public Health
Dent 2003, 63, 52–60.
